6-Substituted purinyl piperazine derivatives useful as cardiotonic and antiarrhythmic agents

ABSTRACT

6-Substituted purinyl piperazine derivatives and a method of synthesis for the derivatives are described. The 6-substituted purinyl piperazine derivatives are useful as cardiotonic agents and antiarrhythmic agents.

BACKGROUND OF THE INVENTION

Field of the Invention

The present application relates to compounds of the formula: ##STR1## asfurther defined herein. The compounds are useful as cardiovascularagents. They possess positive ionotropic activity and are especiallyuseful as cardiotonic agents for improving cardiac ejection,particularly in the setting of acute or chronic heart failure. Thecompounds are also useful as antiarrhythmic agents for the treatment orprevention of cardiac arrythmias.

Description of the Prior Art

British patent application No. GB2186573 and German patent applicationNo. DE3703633 relate to purine derivatives possessing cardiotonic andantiarrhythmic activity and having the following formula: ##STR2##wherein R is an optionally substituted diphenylalkyl group. The sidechain in the above formula is bonded to a ring nitrogen atom.

U.S. Pat. No. 4,460,586 relates to 3-aminopropoxyaryl derivatives of theformula: ##STR3##

The compounds are useful as cardiotonic, antiarrhythmic and α- andβ-adrenoceptor blocking agents. The U.S. patent is one of a series ofpatents that have issued claiming various 4-substituted indolederivatives.

SUMMARY OF THE INVENTION

The present invention is directed to 6-substituted purinyl piperazinederivatives of the general formula: ##STR4## wherein X is S, O, NH andNR₁ wherein R₁ is C₁ -C₄ - lower alkyl;

M is CH₂, CHOH, CHOCOR₂ and CHOR₂ wherein R₂ is straight or branchedchain C₁ -C₈ - lower alkyl, phenyl and substituted phenyl wherein thesubstitutent on the phenyl ring is C₁ -C₄ - lower alkyl, CF₃, halo suchas fluoro, chloro, bromo and iodo, C₁ -C₄ - lower alkyl, C₁ -C₄ - loweralkoxy, NO₂ and CN;

Y is nitrogen, N(CH₂)_(n) wherein n is an integer from 0-4 or a carbonatom having a double bond (C═) attached to the carbon atom to which Ar₁,Ar₂ and Ar₃ are attached;

Ar₁, Ar₂ and Ar₃ are independently selected from H, C₁ -C₄ - loweralkyl, phenyl, substituted phenyl wherein the substituent is C₁ -C₄ -lower alkyl, C₁ -C₄ - lower alkoxy, CF₃, halo and perhalo such asfluoro, chloro, bromo and iodo, NO₂, CN; naphthyl, pyridyl and thienyl;

Z is H, CN, C₁ -C₄ - lower alkyl, halo such as fluoro, chloro, bromo andiodo, OH, CO₂ R₃ wherein R₃ is H or C₁ -C₄ - lower alkyl, phenyl andsubstituted phenyl wherein the substituent is C₁ -C₄ - lower alkyl, NO₂,halo such as chloro, bromo, iodo or fluoro, CN and CF₃ ;

R is H, C₁ -C₄ - lower alkyl, cyclopentyl, cyclohexyl, benzyl, C₂ -C₆ -lower alkenyl, C₂ -C₆ - lower alkynyl, tetrahydropyranyl andtetrahydrofuranyl;

Q is halo such as fluoro, bromo, chloro and iodo; amino, C₁ -C₄ - loweralkyl and OH.

Also included are the optically active isomers of the 6-substitutedpurinyl piperazine derivatives.

In the above general formula at least one of Ar₁ Ar₂ and Ar₃ is anaromatic group and when Y is a carbon atom attached to a double bond(C═) only Ar₁ and Ar₂ are attached to the carbon atom.

The compounds of the general formula are useful as cardiovascularagents, and in particular as cardiotonic agents, and are also useful asantiarrhythmic agents.

DETAILED DESCRIPTION OF THE INVENTION

The invention in its broadest aspects relates to 6-substituted purinylpiperazine derivatives which exhibit positive inotropic activity.

The compounds of the present invention wherein X is sulfur can beprepared as outlined in Scheme 1. ##STR5##

In this case, the appropriately substituted 6-mercaptopurine derivative1 is treated with a base such as amines (for example, triethylamine),metal hydroxides (for example, sodium or potassium hydroxide), metalhydrides (for example, sodium hydride) in an inert solvent such asdimethylformamide (DMF) or tetrahydrofuran (THF). The anion so formed isreacted with appropriately substituted alkylating agents such as thechloride 2 or the epoxide 3 and the reactants are allowed to react forabout 2 to 200 hours at a temperature of about 0° to 100° C. to form thecompounds of the invention 4. The chlorides 2 and epoxides 3 used as thealkylating agents are either commercially available or they can beprepared by procedures found in the chemical literature and available tothose skilled in the art.

Alternatively, the compounds of the present invention wherein X issulfur (S), NH, NR₁ or oxygen (O) can be prepared by the procedureoutlined in Scheme 2. An appropriately substituted purine 5 having asuitable leaving group (L) in the 6-position on the six membered ring isreacted with an appropriately substituted alcohol 6 where X is oxygen,with an amine where X is NH, NR₁, or with a mercaptan, where X issulfur, in a suitable solvent such as benzene, toluene, DMF, DMSO orTHF, for example. As the leaving group (L) a chloro, bromo or tosylgroup may be employed. The purine starting material may or may not besubstituted at the N-9 position. The reaction may be carried out in thepresence of a base and/or a catalyst. Suitable bases which can beemployed include alkali metal and alkaline earth metal hydroxides andhydrides such as sodium or potassium hydroxide, and sodium or potassuimhydride, and sodium or potassuim metal. The reaction may also be carriedout in the presence of a phase transfer or a crown ether catalyst suchas 18-crown-6, for example. When the group at N-9 is a protecting groupit can be removed by acid (in the case where R is tetrahydropyranyl ortetrahydrofuranyl) or hydrogenolysis (in the case where R is benzyl).##STR6##

The compounds of the present invention can also be prepared as outlinedin Scheme 3. An appropriately substituted alcohol 8 is reacted with anacid chloride, such as acetyl chloride or propionyl chloride, forexample, or the corresponding acid anhydride in the presence of a basesuch as, for example, triethylamine or pyridine, in a suitable solventsuch as THF or methylene chloride, for example, to form the esterderivative 9 (R₄ is COR₂ wherein R₂ is as defined above). If an alkyliodide such as methyl iodide, for example, is employed as the alkylatingagent, the reaction is generally carried out in the presence of a strongbase such as sodium hydroxide or sodium hydride, for example, to formthe ether derivatives 10 (R₄ = R₂ wherein R₂ is as defined above). Inthose cases where R is tetrahydropyranyl, for example, the protectinggroup may be removed by hydrolysis with mild acid such as dilutehydrochloric acid.

The compounds of the present invention wherein X is sulfur can also beprepared as outlined in Scheme 4 where an appropriately substituted6-mercaptopurine derivative 1 is treated with epichlorohydrin orglycidyl tosylate in either its racemic or optically active [(2R)-(-) or2S-(+)] form in a suitable solvent, such as ethanol, acetonitrile, DMFor DMSO. The reaction is carried out at a temperature of about 0°-50° C.for a period of about several hours to about 10 days to give thechloride derivative 11. The reaction may optionally be carried out inthe presence of a base such as sodium bicarbonate. Treatment of thechloride derivative 11 with an appropriately substituted benzhydrylpiperazine 12 either neat or in the presence of a solvent at atemperature of about 15°-50° C. for from about several hours to severalweeks results in the purinyl piperazine derivative 13 as racemic oroptically active forms. Suitable solvents that can be employed in thereaction include methanol, ethanol, DMF and DMSO. ##STR7##

The benzhydryl piperazine compounds 12 are available commercially orthey can be prepared according to literature procedures known to thoseskilled in the art. Unsymmetrical triaryl compounds may be prepared byreacting an aromatic carboxylic acid derivative such as ethyl2-naphthalenecarboxylate with an organometallic reagent such as2-pyridyl lithium under controlled conditions to give 2-naphthyl2-pyridyl ketone. This in turn may be reacted with an organometallicreagent such as 2-thienyl lithium to give1-(2-naphthyl)-1-(2-pyridyl)-1-(2-thienyl)methanol. This alcohol may inturn be reacted with halogenating agents such as thionyl chloride togive the corresponding chloromethane derivative in a manner similar tothat described in Procedure 12. Reaction with piperazine in a likemanner as described in Procedure 12 gives the requisite piperazinederivative. By varying the aromatic carboxylic acid derivative and thechoice of the organometallic reagents in this procedure, a variety oftris- and bis-unsymmetrical benzhydryl piperazine derivatives may beprepared.

Pharmaceutical compositions containing a compound of the presentinvention as the active ingredient in intimate admixture with apharmaceutical carrier can be prepared according to conventionalpharmaceutical compounding techniques. The carrier may take a widevariety of forms depending on the form of preparation desired foradministration, e.g., intravenous, oral or parenteral. The compositionmay also be administered by means of an aerosol. In preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like in thecase of oral liquid preparations (such as, for example, suspensions,elixirs and solutions); or carriers such as starches, sugars, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike in the case of oral solid preparations (such as, for example,powders, capsules and tablets). Because of their ease in administration,tablets and capsules represent the most advantageous oral dosage unitform, in which case solid pharmaceutical carriers are obviouslyemployed. If desired, tablets may be sugar-coated or enteric-coated bystandard techniques. For parenterals, the carrier will usually comprisesterile water, though other ingredients, for example, to aid solubilityor for preservative purposes, may be included; injectable suspensionsmay also be prepared, in which case appropriate liquid carriers,suspending agents and the like may be employed. The pharmaceuticalcompositions will generally contain a dosage unit, e.g., tablet,capsule, powder, injection, teaspoonful and the like, from about 0.01 toabout 50 mg/kg, and preferably from about 0.1 to about 10 mg/kg of theactive ingredient.

The following examples describe the invention in greater particularityand are intended to be a way of illustrating but not limiting theinvention. Some of the compounds in the examples were obtained as thehydrate. The water can be removed from the hydrates by drying attemperatures below the melting point of the compound.

EXAMPLE 16-[1-[1-[Bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purineHemihydrate

To DMF (7 mL), 6-mercaptopurine (5 mmol, 0.85 g) was added in portionsand the solution was stirred at room temperature, under N₂ for 5 min.Et₃ N (5 mmol, 0.69 mL) was added dropwise. After 5 min,1-(1-chloro-2-hydroxy-3-propanyl)-4-[bis(4-fluorophenyl)-methyl]-piperazine(5 mmol, 1.9 g) in DMF (5 mL) was added dropwise over 5 min at roomtemperature under N₂. After 22 h, the solution was filtered through asintered glass funnel and the filtrate was evaporated (1.0 mm Hg, 50°C., stirring). Silica gel flash chromatography of the crude product(2.34 g) using 10% MeOH:CH₂ Cl₂ Cl₂ gave pure product, 0.630 g (25.4%),mp 115°-116° C. (dec). DCI/MS (M+1) 497. 400 MHz ¹ H NMR (CDCl₃) δ:8.6(s, 1H), 8.25 (s, 1H), 7.35 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 4.15 (m,1H), 3.45 and 3.6 (m, 2H), 2.65 (m, 2H), 2.6 (m, 4H), 2.4 (m, 4H).

Anal. Calcd. for C₂₅ H₂₆ F₂ N₆ OS•1/2H₂ O: C, 59.40; H, 5.38; N, 16.62.Found: C, 58.88; H, 5.34; N, 16.56.

EXAMPLE 2(2S)-(+)-6-[1-[1-[Bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine

To NaH (0.56 g, 11.6 mmol, 50% suspension in mineral oil prewashed withpentane) in DMF (12 mL) at 0° C. 6-mercaptopurine (1.97 g, 11.6 mmol)was added in portions over 10 min.(2S)-(-)-(1,2-Epoxypropyl)-4-[bis(4-fluorophenyl)methyl]piperazine (4.0g, 11.6 mmol) in DMF (10 mL) was added dropwise at 0° C. over a 5 minperiod. The reaction mixture was allowed to warm to room temperatureafter an additional 5 min and was stirred for 72 h. DMF was removed invacuo (1 mm Hg, 55° C.) and the residue was dissolved in CH₂ Cl₂ (100mL). The solution was filtered through celite, concentrated and theresidue was purified by flash chromatography on silica gel using 10%MeOH:CH₂ Cl₂ to give the title compound as a white solid, 1.37 g (23%),mp 118°-120° C. (dec.); DCI/MS (M+1) 497. 400 MHz ¹ H NMR (CDCl₃) δ:8.65 (s, 1H), 8.2 (s, 1H), 7.35 (m, 4H), 6.98 (m, 4H), 4.2 (s, 1H), 4.18(m, 1H), 3.65-3.45 (m, 2H), 2.7-2.4 (m, 10H); [δ]_(D) ²² +7.3° (0.5% inEtOH).

Anal. Calcd. for C₂₅ H₂₆ F₂ N₆ OS: C, 60.46; H, 5.28; N, 16.92. Found:C, 60.12; H, 5.43; N, 16.94.

EXAMPLE 3(2R)-(-)-6-[1-[1-[Bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine

In a manner similar to Example 2, when(2R)-(+)-(1,2-epoxypropyl)-4-[bis(4-fluorophenyl)methyl]-piperazine(2.18 g, 6.33 mmol) was used, the title compound was isolated as a whitecrystalline solid, 0.61 g (20%), mp 118°-120° C. (dec.); DCI/MS (M+1)497. 400 MHz ¹ H NMR (CDCl₃) δ: 8.63 (s, 1H), 8.20 (s, 1H), 7.32 (m,4H), 6.95 (m, 4H), 4.20 (s, 1H), 4.15 (m, 1H), 3.55 (m, 2H), 2.7-2.4 (m,10H); [δ]_(D) ²² -7.3° (0.5% in EtOH).

Anal. Calcd. for C₂₅ H₂₆ F₂ N₆ OS: C, 60.46; H, 5.28; N, 16.92. Found:C, 60.31; H, 5.71; N, 16.53.

EXAMPLE 46-[2-Hydroxy-3-(1-(diphenylmethyl)piperazin-4-yl)propan-1-yl]thiopurineHemihydrate

To DMF (6 mL), sodium hydroxide pellets (200 mg, 5 mmol) and6-mercaptopurine monohydrate (0.85 g, 5 mmol) were added. The reactionmixture was stirred and heated to 80° C. for 30 min under nitrogen. Thealmost clear solution was cooled to room temperature and1-(1-chloro-2-hydroxy-3-propanyl)-4-(diphenylmethyl)piperazine (1.72 g,5 mmol) in DMF (10 mL) was added within 5 min. After stirring undernitrogen for 72 h, the mixture was filtered through Celite on a sinteredglass funnel and the funnel was rinsed with DMF (2×5 mL). Evaporation ofthe solvent from the filtrate at 1.0 mm Hg at 50° C. gave a residuewhich was triturated with 10% methanol/methylene chloride. Filtrationremoved unreacted 6-mercaptopurine (0.5 g). The solution was purifiedusing flash chromatography on silica gel using 10% methanol/methylenechloride as eluant. The product was isolated by concentration of thedesired fractions and purified by trituration with n-pentane to give thetitle compound (0.35 g, 15.0%), mp 105°-110° C. (dec). DCI/MS M+1 461.100 MHz ¹ H NMR (DMSO-d₆) δ: 8.6 (s, 1H), 8.18 (s, 1H), 7.2-7.4 (m,10H), 4.21 (s, 1H) 4.20 (m, 1H), 3.5 (m, 2H), 2.6 (m, 2H), 2.5-2.6 (m,8H).

Anal. Calcd. for C₂₅ H₂₈ N₆ OS•1/2H₂ O: C, 63.94; H, 6.22; N, 17.90.Found: C, 64.04; H, 6.51; N, 17.86.

EXAMPLE 56-[1-[1-(Benzyl)piperazin-4-yl]-2-hydroxy-3-propanylthio]purineMonomalonate•5/2 Hydrate

6-Mercaptopurine (0.85 g, 5 mmol) and Et₃ N (0.7 mL), 5 mmol) were addedto DMF (7 mL). After 10 min,1-(1-chloro-2-hydroxy-3-propanyl)-4-benzylpiperazine (1.27 g, 5 mmol) inDMF (10 mL) was added dropwise over 5 min under nitrogen. After 96 h theDMF was removed in vacuo to give the crude product (1.99 g). Flashchromatography using silica gel and 10% MeOH:CH₂ Cl₂ gave pure base(1.01 g, 52.6%). To this white solid (700 mg, 1.82 mmol) dissolved inMeOH (5 mL) malonic acid (0.96 M, 1.82 mmol, 1.9 mL) was added dropwiseover 5 min under nitrogen. After 5 h, the MeOH was removed in vacuo andthe resultant solid was dried further under vacuum at 40° C. to give thepure title compound (0.860 g, 92.76%, overall yield 48.8%), mp 175° C.(dec.) DCI/MS (M+1) 385. 400 MHz ¹ H NMR (DMSO-d₆) δ: 8.7 (s, 1H), 8.4(s, 1H), 7.35 (M, 5H), 4.1 (m, 1H), 3.7 (s, 2H), 3.4-3.6 (m, 2H), 2.95(s, 2H), 2.5-2.9 (m, 10H).

Anal. Calcd. for C₁₉ H₂₄ N₆ OS•C₃ H₄ O₄ •5/2H₂ O: C, 49.52; H, 6.23; N,15.75. Found: C, 49.58; H, 5.95; N, 15.55.

EXAMPLE 66-[3-[4-(1,3-Benzodioxol-5-yl)methyl]piperazin-1-yl]-2-hydroxyprop-1-ylthio]purineSesquihydrate

6-Mercaptopurine (0.850 g, 5 mmol) and Et₃ N (0.7 mL, 5 mmol) were addedto DMF (7 mL). After 10 min,1-(1-chloro-2-hydroxy-3-propanyl)-4-piperonylpiperazine (1.56 g, 5 mmol)in DMF (10 mL) was added dropwise over 5 min under nitrogen. After 96 hand removal of the precipitated NaCl by filtration, the DMF was removedin vacuo to give the crude product (1.99 g). Flash chromatography usingsilica gel and 10% MeOH:CH₂ Cl₂ gave the pure product (1.01 g, 47.2%) asa white solid, mp 138°-140° C. DCI/MS (M+1) 429.400 MHz ¹ H NMR(DMSO-d₆) δ: 8.65 (s, 1H), 8.45 (s, 1H), 6.85 & 6.75 (m, 3H), 6.0 (s,2H), 3.95 (m, 1H), 3.70 (m, 2 H), 3.35 (s, 1H), 3.30 (m, 2H), 2.3-2.6(m, 8H).

Anal. Calcd. for C₂₀ H₂₄ N₆ O₃ S•3/4H₂ O: C, 52.74; H, 5.97; N, 18.45.Found: C, 52.98; H, 5.56; N, 18.40.

EXAMPLE 76-[1-[1-(4-Chlorobenzhydryl)]piperazin-4-yl]-2-hydroxy-3-propanylthio]purineMonohydrate

6-Mercaptopurine (0.850 g, 5 mmol) and Et₃ N (0.7 mL, 5 mmol) were addedto DMF (7 mL). After 10 min,1-(1-chloro-2-hydroxy-3-propanyl)-4-(4-chlorobenzhydryl)piperazine (1.9g, 5 mmol) in DMF (10 mL) was added dropwise over 5 min at roomtemperature under nitrogen. After 7 days, the resultant solution wasfiltered and the DMF removed in vacuo giving the crude product (2.5 g).Silica gel flash chromatography using 10% MeOH:CH₂ Cl₂ gave the desiredproduct (1.0 g, 40.5%) as a white solid; mp 117°-120° C. (dec). DCI/MS(M+1) 495. 400 MHz ¹ NMR (CDCl₃) δ: 8.6 (s, 1H), 8.2 (s, 1H), 7.35 (m,4H), 7.2 (m, 4H), 4.25 (m, 1H), 4.2 (s, 1H), 3.4-3.6 (m, 2H), 2.8 (m,6H), 2.4 (m, 4H).

Anal. Calcd. for C₂₅ H₂₇ ClN₆ OS•H₂ O: C, 58.55; H, 5.70; N, 16.39.Found: C, 58.86; H, 5.53; N, 16.35.

EXAMPLE 86-[1-[1-(Triphenylmethyl)piperazin-4-yl]-2-hydroxy-3-propanylthio]purineMonohydrate

1-(1-Chloro-2-hydroxy-3-propoxy)-4-(triphenylmethyl) piperazine (2.3 g,5.5 mmol) was reacted as above with with 6-mercaptopurine to give thetitle compound as an off-white solid, 0.63 g (21.3%), mp 158°-161° C.DCI/MS (M+1) 537. 400 MHz ¹ H NMR (CDCl₃) δ:8.55 (s, 1H), 8.15 (s, 1H),7.45 (m, 4H), 7.25 (m, 4H), 4.15 (m, 1H), 4.15 (m, 1H), 3.59 (dd, 1H,J═4.85 Hz), 3.45 (dd, 1H, J═7.27 Hz), 2.8-2.4 (m, 10H).

Anal. Calcd. for C₃₁ H₃₂ N₆ OS•H₂ O: C, 67.12; H, 6.18; N, 15.15. Found:C, 67.29; H, 5.91; N, 14.96.

EXAMPLE 96-[1-[1-(Carboethoxy)piperazin-4-yl]-2-hydroxy-3-propanylthio]purine

1-(1-Chloro-2-hydroxy-3-propoxy)-4-carboethoxypiperazine (1.24 g, 5.0mmol) was reacted as above with 6-mercaptopurine to give the titlecompound as a clear oil, 120 mg (6.54%). DCI/MS (M+1) 367. 400 MHz ¹ HNMR (CDCl₃) δ: 8.7 (s, 1H), 8.2 (s, 1H), 4.15 (q, 2H, J═4.85 Hz), 3.6(m, 2H), 3.5 (m, 4H), 2.6 (m, 4H), 2.45 (m, 2H), 2.25 (t, 3H, J═4.85Hz).

Anal. Calcd. for C₁₅ H₂₂ N₆ O₃ S: C, 49.17; H, 6.05; N, 22.93. Found: C,49.35; H, 6.24; N, 22.09.

EXAMPLE 106-[1-[l-(3,4'[Bis(trifluoromethylphenyl)methyl])piperazin-4-yl]-2-hydroxy-3-propanylthio]purine

1-(1-Chloro-2-hydroxy-3-propoxy)-4-[bis(3,4'-trifluoromethylphenyl)methyl]piperazine(1.0 g, 2.1 mmol) was reacted as above with 6-mercaptopurine to give thetitle compound as an off-white solid, 160 mg g (12.8%), mp 108°-110° C.DCI/MS (M+1) 597. 400 MHz ¹ H NMR (CDCl₃) δ: 8.65 (s, 1H), 8.3 (s, 1H),7.65 (s, 1H), 7.59-7.4 (m, 7H), 4.39 (s, 1H), 4.15 (m, 1H), 3.65 (dd,1H, J═4.86 Hz), 3.5 (dd, 1H, J═7.29 Hz), 2.7-2.4 (m, 10H).

Anal. Calcd. for C₂₇ H₂₆ F₆ N₆ OS: C, 54.37; H, 4.39; N, 13.99. Found:C, 54.42; H, 4.21; N, 14.09.

EXAMPLE 116-[1-[1-[Bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-acetoxy-3-propanylthio]purine3/4 Hydrate

To a solution of6-[1-[1-[bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine(1.0 g, 0.002 mol) in CH₂ Cl₂ (7 mL), acetic anhydride (0.2 mL, 0.002mol) in Et₃ N (0.2 mL, 0.002 mol) was added dropwise over 5 min at roomtemperature under nitrogen. After 70 h, CH₂ Cl₂ (50 mL) was added andthe solution was extracted with saturated NaHCO₃ (2×100 mL), H₂ O (1×100mL), and saturated brine (1×100 mL); the organic layer was dried overNa₂ SO₄. Solvent removal of the dried organic layer gave a solid whichwas dried in vacuo at 40° C. to give pure product (0.7 g, 64.8%), mp105°-109° C. (dec). DCI/MS (M+1) 539. 400 MHz ¹ H NMR (CDCl₃) δ: 8.7 (s,1H), 8.2 (s, 1H), 7.3 (m, 4H), 6.95 (m, 4H), 5.3 (m, 1H), 4.2 (s, 1H),3.4 and 4.0 (m, 2H), 2.65 (m, 2H), 2.6 (m, 4H), 2.4 (m, 4H), 2.0 (s,3H).

Anal. Calcd. for C₂₇ H₂₈ F₂ N₆ O₂ S•3/4 H₂ O: C, 58.74; H, 5.38; N,15.22. Found: C, 58.69; H, 5.37; N, 15.02.

EXAMPLE 126-[1-[1-[Bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-(2,2,2-trimethylacetoxy)propanylthio]purine

To6-[1-[1-[bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine(4.04 g, 8 mmol) in CH₂ Cl₂ (5 mL), trimethylacetic anhydride (8 mmol,1.62 mL) in Et₃ N (1.15 mL, 8 mmol) was added dropwise under nitrogen.After 21 h an additional equivalent of the anhydride was added. After 92h and silica gel flash chromatography (10% MeOH:CH₂ Cl₂) of the solventfree residue, crude product was obtained. The crude product wasdissolved in CH₂ Cl₂ (10 mL) and stirred with saturated NaHCO₃ (10 mL)for 16 h. The CH₂ Cl₂ was separated and extracted with H₂ O (1×) andsaturated NaCl (1×), dried over Na₂ SO₄ and the CH₂ Cl₂ removed in vacuoto give pure product (0.88 g, 37.5%) as a white solid. mp 102°- 104° C.(dec.). DCI/MS (M+1) 581. 400 MHz ¹ H NMR (CDCl₃) δ: 8.7 (s, 1H), 8.2(s, 1H), 6.95 (m, 4H), 7.35 (m, 4H), 5.4 (m, 1H), 4.2 (s, 1H), 3.5 and4.0 (m, 2H), 2.65 (m, 2H), 2.4 & 2.6 (m, 8H), 1.15 (S, 9H).

Anal. Calcd. for C₃₀ H₃₄ F₂ N₆ O₂ S: C, 62.05; H, 5.90; N, 14.47. Found:C, 61.85; H, 5.98; N, 14.04.

EXAMPLE 136-[1-[1-[Bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-(3,4,5-trimethoxybenzoyloxy)-3-propanylthio]purine

Trimethoxybenzylchloride (0.92 g, 4 mmol) in Et₃ N (0.4 mL, 4 mmol) andCH₂ Cl₂ (2 mL) were added dropwise at 0° C. to6-[1-[1-[bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine(2 g, 4 mmol) in CH₂ Cl₂ (3 mL). After 16 h the solution was filteredand the filtrate concentrated in vacuo followed by silica gel flashchromatography (10% MeOH:CH₂ Cl₂) to give crude product (2.23 g). Thecrude product was dissolved in ether (50 mL) and pentane (10 mL) and theresultant precipitate isolated as a white solid, (0.83 g, 30.0%), mp114°-118° C. (dec). DCI/MS (M+1) 691. 400 MHz ¹ H NMR (CDCl₃) δ: 8.55(s, 1H), 8.15 (s, 1H), 6.95-7.3 (m, 8 H), 7.2 (s, 2H), 5.78 (m, 1H), 4.2(s, 1H), 3.9 (s, 1H), 3.8 (s, 2H), 3.4 (m, 2H), 2.5-2.4 (m, 8H).

Anal. Calcd. for C₃₅ H₃₆ F₂ N₆ O₅ S: C, 60.86; H, 5.25; N, 12.17. Found:C, 60.65; H, 5.32; N, 12.01.

EXAMPLE 146-[1-[1-[Bis(4-fluorophenyl)methyl]piperazin-4-yl]-3-propanylthio]purine

Pentane (10 mL) was added to sodium hydride (0.3 g, 6.3 mmol, 50%suspension in mineral oil), and the mixture was stirred under nitrogen.The pentane was decanted, anhydrous DMF (12 mL) was added and thesuspension was cooled to 0° C. 6-Mercaptopurine monohydrate (0.93 g, 5.5mmol) was added in small portions over a 15 min period. To the lightbeige, slightly hazy mixture was added, after an additional 10 min at 0°C., 1-(1-chloro-3-propanyl)-4-[bis(4-fluorphenyl)methyl]piperazine (2.0g, 5.5 mmol) dissolved in anhydrous DMF (4mL) within 5 min. Afteraddition was complete, the mixture was allowed to warm to roomtemperature and it was stirred under nitrogen for 4 days. The DMF wasevaporated in vacuo (1 mm Hg) at 50° C. The residue was triturated inmethylene chloride and the mixture was filtered through celite. Thefiltrate was washed with water (2×50 mL), dried (sodium sulfate),filtered, and evaporated in vacuo to give the crude product (2.79 g).Silica gel flash chromatography using 10% methanol/methylene chloridegave the desired product (1.18 g, 45%) mp 90°-93° C. 300 MHz ¹ H NMR(CDCl₃) δ: 8.60 (s, 1H), 8.14 (s, 1H), 7.31 (m, 4H), 6.95 (m, 4H), 4.17(s, 1H), 3.38 (m, 2H), 2.35-2.6 (m, 10H), 2.02 (m, 2H). DCI/MS (M+1)481.

Anal. Calcd. for C₂₅ H₂₆ F₂ N₆ S: C, 62.61; H, 5.25; N, 17.53. Found: C,62.38; H, 5.46; N, 17.62.

EXAMPLE 156-[1-[4-[Bis(4'-fluorophenyl)methylene]-1-piperidinyl]-2-hydroxy-3-propanylthio]purineHemihydrate

To benzyl 4-[bis(4-fluorophenyl)methylene]-1-piperidine (8.0 g, 21 mmol)dissolved in MeOH (140 mL), 10% Pd/C (4.0 g) dispersed in MeOH was addedunder nitrogen, followed by the addition of ammonium formate (6.3 g, 100mmol). The reaction mixture was stirred and refluxed. The resultantsolution was filtered over celite under nitrogen. Evaporation in vacuogave an oil which solidified upon standing overnight to give thedebenzylated piperidine derivative (5.99 g, 100%).

To the piperidine derivative isolated above (6.0 g, 21 mmol) dissolvedin EtOH (60 mL) with NaHCO₃ (1.8 g, 21 mmol) epichlorohydrin (1.7 mL, 22mmol) in EtOH (20 mL) was added dropwise at 0° C. under nitrogen. After30 min the reaction mixture was allowed to come to room temperature.After 24 h, removal of the EtOH in vacuo gave the crude product (7.86g). Silica gel flash chromatography using 10% MeOH:CH₂ Cl₂ gave the purechloropropyl derivative (4.0 g, 50%).

To NaH (280 mg, 5.8 mmol, 50% suspension in mineral oil, pentane washedand removed) in DMF (12 mL) at 0° C. was added 6-mercaptopurine (850 mg,5 mmol) was added in portions over 15 min, under nitrogen. After 1 h,the chloride obtained above (2.08, 5 mmol) in DMF (14 mL) was added over15 min at 0° C., under nitrogen. The reaction mixture was allowed towarm to room temperature for 3 days and then was heated to 70° C. undernitrogen for 1 day. Solvent removal in vacuo and extraction of theresidue with CH₂ Cl₂ gave crude product (2.4 g). Silica gel flashchromatography using 10% MeOH:CH₂ Cl₂ gave the title compound (1.28 g).Further trituration of this product with pentane (100 mL) gave pureproduct (0.73 g, 29.2%), mp 107°-110° (dec). DCI/MS (M+ 1) 494. 400 MHz¹ H NMR (CDCl₃) δ: 8.65 (s, 1H), 8.25 (s, 1H), 7.16 (m, 4H), 6.9 (m,4H), 4.2 (m, 1H), 3.55-3.65 (m, 2H), 2.4-2.7 (m, 2H).

Anal. Calcd. for C₂₆ H₂₅ F₂ N₅ OS•1/2H₂ O: C, 62.13; H, 5.21; N, 13.94.Found: C, 62.24; H, 4.80; N, 14.38.

EXAMPLE 166-[1-[1-[Bis(4-chlorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine•5/4Hydrate

Et₃ N (0.7 mL, 5 mmol) was added to 6-mercaptopurine (0.85 g, 5 mmol) inDMF (7 mL). After 5 min1-(1-chloro-2-hydroxy-3-propanyl)-4-]bis(4-chlorophenyl)-methylpiperazine(2.07 g, 5 mmol) in DMF (13 mL) was added dropwise over 5 min, undernitrogen. After 14 days and filtration of the resultant NaCl the DMF wasremoved in vacuo to give the crude product. Silica gel flashchromatography using 10% MeOH:CH₂ Cl₂ gave the desired product (0.710 g)containing some DMF. The product was dissolved in CH₂ Cl₂ (100 mL) andextracted with H₂ O (2×25 mL) and saturated NaCl (1×25 mL), dried overNa₂ SO₄, and the CH₂ Cl₂ removed in vacuo to give pure product (0.590 g,22.3%), mp 120°-124° C. (dec.) DCI/MS (M+1) 529. 400 MHz ¹ H NMR (CDCl₃)δ: 8.6 (s, 1H), 8.2 (s, 1H), 7.25 (m, 8H), 4.2 (s, 1H), 4.1 (m, 1H), 3.6(m, 2H), 2.7 (m, 2H), 2.3-2.6 (m, 8H).

Anal. Calcd. for C₂₅ H₂₆ Cl₂ N₆ OS•5/4H₂ O: C, 54.39; H, 5.20; N, 15.22.Found: C, 54.03; H, 4.76; N, 14.91.

EXAMPLE 176-[3-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]-2-hydroxypropoxy]-9-(tetrahydropyran-2-yl)purine

To a stirred mixture of 6-chloro-9-(tetrahydro-2-pyranyl)purine (2.387g, 10 mmol) in toluene (40 mL), powdered KOH (1.22 g, 21.4 mmol) and18-crown-6 (0.132 g, 0.5 mmol) a solution of 3-[4-[di(4-fluorophenyl)methyl]-1-piperazinyl]-1,2-propanediol (3.8 g, 10.25mmol) in toluene (80 mL) was added dropwise over a period of 5 min.After 3 h of stirring at room temperature the reaction mixture wastreated with ice-cold water (70 mL). The organic layer was separated andwashed with ice-water (4×70 mL), dried (Na₂ SO₄), filtered andevaporated in vacuo to yield a foam (about 6 g) which was eluted througha silica gel column at medium pressure using increasing proportions ofMeOH in CH₂ Cl₂ as eluant. The fractions were pooled to give severalmajor components. The faster moving fraction (I) was the bis-purinylcompound (1.14 g,). The middle fraction was the title compound (1.26 g,colorless foam) which softened at 115° C. and melted 120°-125° C.IR(KBr) cm⁻¹ : 3400, 1602, 1578, 1506, 1341, 1224; ¹ H NMR (CDCl₃) δ:8.52 (s, 1H, 2 or 8-H), 8.14 (s, 1H, 2 or 8-H), 6.9-7.4 (m, 8H, Ar-H),5.76 (d, 1H, N-CH-O-C), 4.63 (m, 2H, OCH₂), 4.21 [s, 1H, CH(O-F)₂ ],4.20 (m, 3.79 (m, 1.5-2.9 (m); MS 565 (MH)+.

Anal. Calcd. for C₃₀ H₃₄ F₂ N₆ O₃ •1/4H₂ O: C, 63.31; H, 6.11; N, 14.77.Found: C, 63.15; H, 5.85; N, 14.88.

EXAMPLE 186-[3-[4-Bis(4-fluorophenyl)methyl]piperazin-1-yl-2-hydroxy]propoxypurine

6-[3-[4-[Bis(4-fluorophenyl)methyl]piperazin-1-yl]-2-hydroxypropoxy]-9-(tetrahydro-2-pyranyl)purine(0.84 g, 1.488 mmol) was dissolved in glacial acetic acid (50 mL) andthe resultant solution was diluted with water (30 mL). The aqueoussolution was stirred at room temperature for 18 h, evaporated to drynessand the residue was treated with saturated aqueous sodium bicarbonate(100 mL). The precipitated solid was collected by filtration and washedwith water and ether. The ether soluble portion of the solid wasrecovered starting material. The ether insoluble portion wasre-extracted with boiling ether/CH₂ Cl₂ (100 mL) and the insoluble solidisolated to give the purified title compound (380 mg, 53%), mp 147°-155°C. IR (KBr) cm⁻¹ : 3327, 3365, 1605, 1506; ¹ H NMR (DMSO-d₆) δ: 8.45 (s,1H, 2 or 8-H), 8.37 (br, 1H, 2 or 8-H), 7.05-7.50 (m, 8H, Ar-H), 4.54(m, 1H, OCHH), 4.38 (m, 1H, OCHH); MS(DCI): 481 (MH)⁺.

Anal. Calcd. for C₂₅ H₂₆ F₂ N₆ O₂ : C, 62.49; H, 5.45; N, 17.49; F,7.91. Found: C, 62.43; H, 5.27; N, 17.64; F, 7.76.

EXAMPLE 196-[3-[4-Diphenylmethyl)piperazin-1-yl]-2-hydroxypropoxy]-9-(tetrahydro-2-pyranyl)purine•1/4Hydrate

To a solution of 6-chloro-9-(tetrahydro-2-pyranyl)purine (2.387 g, 10mmol) in toluene (50 mL) were added potassium hydroxide (1.22 g, 21.4mmol), 18-crown-6 (0.132 g, 0.05 mmol), and2-[(4-phenylmethyl)-1-piperazinyl]-1, -2-propanediol (3.346 g, 10.25mmol); the mixture was stirred vigorously for 2 h at room temperatureand was heated to 90° C. for 14 h. After cooling, the reaction mixturewas washed with water (4×100 mL); the organic layer was dried (Na₂ SO₄),filtered and evaporated to dryness in vacuo to yield a foam (4.48 g).Purification on a silica gel column eluting with increasing proportionsof MeOH in CH₂ Cl₂ gave several fractions consisting of a mixture ofseveral components; one set of fractions contained the title compoundwhich was isolated as a foam, (0.63 g), mp: 90° C. (softening),100°-110° C. melting. IR(KBr) cm⁻¹ : 3420, 1601, 1317; ¹ H NMR (CDCl₃)δ: 8.58 (s, 1H, 2 or 8-H), 8.41 (s, 1H, 2 or 8-H), 7.1-7.45 (m, 10H,Ar-H), 5.74 (m, 1H, N-CH-O-C), 4.58 (m, 2H, O-CH₂), 4.22 [s, 1H, CH(O)₂], 4.13 and 2.80 (br s each, 1H, OCH₂) 1.5-2.7 (br m, 16 H, N-CH₂ andOCH₂); MS: 529 (MH)+.

Anal. Calc. for C₃₀ H₃₆ N₆ O₃ •1/4H₂ O: C, 67.50; H, 6.90; N, 15.76.Found: C, 67.25; H, 6.70; N, 15.99.

EXAMPLE 206-[3-[4-(Diphenylmethyl)piperazin-1-yl]-2-hydroxypropoxy]-purine

6-[3-[4-Diphenylmethyl)piperazin-1-yl]-2-hydroxy-propoxy]-9-(tetrahydro-2-pyranyl)purine(0.89 g, 1.68 mmol) was dissolved in glacial acetic acid (60 mL) and theresultant solution was diluted with water (40 mL). The aqueous solutionwas stirred at room temperature for 64 h and the reaction mixture wasevaporated to dryness in vacuo. The residue was treated with 5% aqueoussodium bicarbonate (40 mL) and the precipitated solid was extracted witha mixture of ether:CH₂ Cl₂ (3:1) (100 mL). The organic layer wasfiltered, washed with water, dried (Na₂ SO₄) and evaporated to give thetitle compound as a colorless foam, 0.59 g (79%), mp. 115° C.(softening), 120°-130° C. (melting). IR (KBr) cm⁻¹ : 3369, 3220, 1604,1338, 1319, 1113; ¹ H NMR (DMSO-d₆) δ: 8.45 (s, 1H, 2 or 8-H), 8.36 (s,1H, 2- or 8-H), 7.1-7.5 (m, 10H, Ar-H), 4.56 (m, 1H, OCHH), 4.37 (m, 1H,OCHH), 4.23 [s, 1H, CH(O)₂ ]; MS: 446 (MH).sup. +.

Anal. Calcd. for C₂₅ H₂₈ N₆ O₂ : C, 67.55; H, 6.35; N, 18.91. Found: C,67.34; H, 6.42; N, 18.99.

EXAMPLE 214-[3-[4-[Bis(4-fluorophenyl)methyl]piperazin-1-yl]-2-hydroxypropylamino]purine

A mixture of 6-chloropurine (0.728 g, 4.7 mmol),1-amino-3-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-2-propanol (1.73g, 4.77 mmol) and triethylamine (1.36 mL, 9.5 mmol) in MeOH (20 mL) washeated to reflux for 7 days and the solvent was removed in vacuo. Theresidue was dissolved in CHCl₃ and the extracted with aqueous sodiumbicarbonate (2×100 mL); the organic phase was dried over sodium sulfateand evaporated to give a solid which was purified by flashchromatography on silica gel with 5% MeOH in CHCl₃. The product was acolorless solid which was triturated with ether, 1.5 g (70%), mp140°-170° C.; IR (KBr) 3000 cm⁻¹ ; 300 MHz ¹ H NMR (CDCl₃); δ: 8.17 (s,1H), 8.11 (s, 1H), 7.5-7.0 (m, 8H), 4.90 (br s, 1H), 4.34 (s, 1H), 3.87(br s, 1H), 3.7-2.0 (m, 12H); MS 480 (MH⁺).

Anal. Calcd. for C₂₅ H₂₇ F₂ N₇ O: C, 62.62; H, 5.68; N, 20.45. Found: C,62.55; H, 5.74; N, 20.10.

EXAMPLE 224-[3-[4-[Bis(4-fluorophenyl)methyl]piperazin-1-yl]-2-acetoxypropylamino]purine•1.75Hydrate

Triethylamine (0.15 mL, 1.08 mmol) and acetic anhydride (0.08 mL, 0.85mmol) were added to a solution of4-[3-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]-2-hydroxypropylamino]purine (350 mg, 0.730 mmol) in CH₂ CL₂ (5 mL) and thesolution was stirred for 18 h. An additional amount of triethylamine(0.11 mL) and acetic anhydride (0.04 mL) was added and the mixture wasstirred an additional 1 h. The mixture was extracted with aqueous sodiumbicarbonate (2×20 mL), dried over sodium sulfate and concentrated togive a glass (0.45 g). Purification on silica gel with 2% MeOH in CHCl₃gave the title compound as a colorless foam, 0.267 g (66%), mp 110°-155°C.; IR (KBr) 1738 cm⁻¹ ; 300 MHz ¹ H NMR (CDCl₃ : δ 8.42 (s, 1H), 7.97(s, 1H), 7.5-6.9 (m, 8H), 5.24 (br s, 1H), 4.23 (s, 1H), 3.87 (br s,1H), 3.7-2.0 (m, 12H), 2.03 (s, 3H); MS 522 (MH³⁰).

Anal Calcd. for C₂₅ H₂₇ F₂ N₇ O•13/4H₂ O: C, 58.63; H, 5.92; N, 17.72.Found: C, 58.75; H, 5.37; N, 17.66.

EXAMPLE 23 CARDIOTONIC ACTIVITY

Adult mongrel dogs were anesthetized with sodium pentobarbital (45mg/kg, i.p.) and artificially respired. Mean arterial pressure (MAP) wasrecorded from a cannulated femoral artery and drugs were infused into acannulated femoral vein. The arterial pressure pulse was used to triggera cardiotachometer for determination of heart rate (HR). Leftventricular pressure was measured with a Millar catheter and dP/dt_(max)was derived. A right thoracotomy was performed and myocardialcontractile force (CF) was measured with a Walton Brodie strain gaugesutured to the right ventricle. The ventricular muscle was stretched toproduce a baseline tension of 100 g. A standard dose of dopamine (10-15ug/kg/min for 3 min) was administered to determine myocardialresponsiveness to inotropic stimulation.

Test compounds were solubilized in a small volume of DMF diluted to afinal concentration of 10% in physiological saline. Alternatively, wherepossible, a soluble hydrochloride salt was prepared by addition of 0.1NHCl diluted in physiological saline. Vehicles were tested in appropriatevolumes and found to exert less than a 5% effect on contractile force.For iv studies, compounds were administered by infusion pump (one drugper animal) at rates of 0.58-2.2 mL/min in three to four stepwiseincreasing doses. Each dose was infused over 5 min immediately after theeffect of the previous dose peaked. MAP, HR, dP/dt_(max) and CFresponses were continuously monitored on a Beckman or Gould recorder andexpressed as a percent change from pre-drug control values vs. thecumulative dose of drug administered. For these studies, n representsthe number of test animals used.

Quantitation of the inotropic potency was obtained by calculation of thecontractile force (CF) ED₅₀. This was defined as the dose of compoundthat produced a 50% increase above baseline in myocardial contractileforce. The value was obtained from three to four point dose-responsecurves using either graphical estimation (n<3) or linear regressionanalysis (n≧3). Data from this evaluation is shown in Table 1. Numbersin parentheses are number of animals screened.

                  TABLE 1                                                         ______________________________________                                        Cardiovascular activity of compounds of the                                   Invention                                                                                   (% from Control)                                                Example                                                                              Dose (mg/kg iv)                                                                            m     MAP    HR    dPdt CF                                ______________________________________                                        1      1.875        5     -5     1-    127  214                                      (ED.sub.50 = 0.16                                                             (0.01-0.35))                                                           2      1.875        3     -13    -6    168  212                                      (Ed.sub.50 = 0.07                                                             (0.05-0.09))                                                           3      1.875        3     -4     -8    91   151                                      (Ed.sub.50 = 0.35                                                             (0.23-0.48))                                                           4      1.875        3     -12    -1    60   86                                5      1.875        1     -3     5     58   43                                6      1.875        1     4      15    80   79                                7      1.875        1     1      0     75   97                                7      1.875        2     -2     -4    75   100                               10     1.875        1     5      0     47   71                                11     1.875        2     -12    -4    62   145                                      (ED.sub.50 450 ug/kg)                                                  14     1.875        4     -6     2     17   38                                15     1.875        2     -14    -7    28   87                                       (ED.sub.50 725 ug/kg)                                                  16     1.875        3     9      -4    99   151                                      (ED.sub.50 608 ug/kg)                                                  17     1.875        1     -13    0     16   37                                18     1.875        2     4      12    58   80                                       (ED.sub.50 825 ug/kg)                                                  19     1.875        1     2      3     19   43                                20     1.875        2     4      2     36   66                                ______________________________________                                    

PROCEDURE 13-[4-[Bis(4-fluorophenyl)methyl]-1-piperazinyl]-1,2-propanediol•0.25Hydrate

To a stirred and warmed solution of 4-fluorobenzhydrylpiperazine (6.343g, 22 mmol) in MeOH (75 mL), a solution of glycidol (1.63 g, 22 mmol) inMeOH (25 mL) was added slowly under nitrogen. The mixture was stirred atroom temperature for 18 h, refluxed for 2 h and evaporated to dryness.CH₂ Cl₂ (4×100 mL) was added to the syrupy residue and the mixture wasevaporated to dryness. The syrupy residue was purified by chromatographyon a silica gel column (medium pressure). Eluting with 2%-5% MeOH/CH₂Cl₂ gave the title compound as a colorless syrup which upon prolongedevacuation formed a hygroscopic foam (5.84 g, 73%), mp 40°-50° C.IR(KBr) cm⁻¹ : 3625, 3575; ¹ H NMR (CDCl₃) δ: 6.9-7.4 (m, 8H, Ar-H);4.21 [s, 1H, CH(O)₂ ], 3.80 (m, 1H, HCOH), 3.73 and 3.49 (each m, each1H, HOCH₂), 3.8-2.3 (m, 10H, N--CH₂); MS(DCI):363 (MH)+.

Anal. Calcd. for C₂₀ H₂₄ F₂ N₂ O₂ •1/4H₂ O: C, 65.46; H, 6.73; N, 7.63.Found: C, 65.09; H, 6.66; N, 7.49.

PROCEDURE 2 3-[4-(Diphenylmethyl)-1-piperazinyl]-1,2-propanediol

In a procedure analogous to that of Procedure 1 above,4-benzyhydrylpiperazine (12.61 g, 0.05 mmol) in MeOH (50 mL) was reactedwith glycidol (3.704 g, 0.05 mmol) in MeOH (20 mL) and worked up to givethe title compound as a colorless crystalline solid, 13.20 g (81%), mp130°-131° C. (mp 125°-126° C. reported by M. Verderame, J. Med. Chem.,11, 1090 (1968)).

Anal. Calcd for C₂₀ H₂₆ N₂ O₂ : C, 73.59; H, 8.03; N, 8.58. Found: C,73.32; H, 8.21; N, 8.48.

PROCEDURE 31-(1-Chloro-2-hydroxy-3-propanyl)-4-[bis(4-fluorophenyl)methyl]piperazineMonohydrate

To a mixture of epichlorohydrin (3.5 mL, 0.05 mol) in ethanol (12 mL) at0° C. (ice bath) and anhydrous NaHCO₃ (4.2 g, 0.05 mol)[bis(4-fluorophenyl)methyl]piperazine (14.4 g, 0.05 mol) in ethanol (200mL) was added dropwise over 45 min under N₂. The ice bath was removedand the mixture was allowed to come to room temperature. After 18 h theNaHCO₃ was removed by filtration via a sintered glass funnel and theethanol in the filtrate was removed in vacuo to give the crude product(21.3 g). Silica gel flash chromatography using 2.0% MeOH:CH₂ Cl₂ gavepure product (10.05 g, 52.9%) as an amber oil. DCI/MS (M+1) 381. 400 MHz¹ H NMR (CDCl₃) δ: 7.3 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 3.95 (m, 1H),3.55 (m, 2H), 2.7 (m, 2H), 2.5 (m, 4H), 2.4 (m, 4H).

Anal. Calcd. for C₂₀ H₂₃ ClF₂ N₂ O•H₂ O: C, 60.22; H, 6.32; N, 7.02.Found: C, 6.29; H, 6.21; N, 6.83.

PROCEDURE 41-(1-Chloro-2-hydroxy-3-propanyl)-4-(diphenylmethyl)piperazine

To a mixture of epichlorohydrin (5.1 mL, 0.065 mL) in ethanol (13 mL)and anhydrous NaHCO₃ (0.065 mol, 5,46 g) at 0° C.,diphenylmethylpiperazine (16.4 g, 0.065 mol) in ethanol (250 mL) wasadded dropwise over 45 min at room temperature under N₂. After 17 h theNaHCO₃ was removed by filtration via a sintered glass funnel and theethanol was removed from the filtrate in vacuo giving a white-yellowsolid (21.5 g). This solid after trituration with Et₂ O (300 mL) gave aprecipitate which was filtered and dried in vacuo to give the pureproduct (5.11 g, 22.8%) mp 114°-116° C. DCI/MS (M+1) 345. 400 MHz ¹ HNMR (CDCl₃) δ: 7.2-7.4 (m, 10H), 4.2 (s, 1H), 3.9 (m, 1H), 3.55-3.7 (m,2H), 2.7 (m, 2H), 2.45 (m, 8H).

Anal. Calcd. for C₂₀ H₂₅ ClN₂ O: C, 69.60; H, 7.20; N, 8.10. Found: C,69.59; H, 7.44; N, 7.96.

PROCEDURE 5 1-(1-Chloro-2-hydroxy-3-propanyl)-4-benzylpiperazine

To a mixture of epichlorohydrin (3.92 mL, 50 mmol) in EtOH (25 mL) andanhydrous NaHCO₃ (4.2 g, 50 mmol) 1-benzylpiperazine (8.66 mL, 50 mmol)in EtOH (100 mL) was added dropwise over 30 min at 0° C. under nitrogen.After 16 h the EtOH was removed in vacuo and the crude product waseluted through silica gel (5% MeOH:CH₂ Cl₂) to give pure product (10.12g, 75.3%) as an amber oil. DCI/MS (M+1) 269. 400 MHz ¹ H NMR (CDCl₃) δ:7.3 (m, 5H), 4.95 (m, 1H), 4.5 and 4.6 (m, 2H), 3.95 (m, 1H), 3.6 (m,2H), 3.5 (s, 2H), 2.7 (m, 4H), 2.4 (m, 4H).

Anal. Calcd. for C₁₄ H₂₁ ClN₂ O: C, 62.50; H, 7.87; N, 10.40. Found: C,62.41; H, 7.83; H, 10.35.

PROCEDURE 6 1-(1-Chloro-2-hydroxy-3-propanyl)-4-piperonylpiperazine

To a mixture of epichlorohydrin (3.9 mL, 50 mmol) in EtOH (25 mL) andanhydrous NaHCO₃ (4.2 g, 50 mmol) 1-piperonylpiperazine (11.0 g, 50mmol) in EtOH (125 mL) was added dropwise over 45 min at 0° C., undernitrogen. After 16 h and removal of the EtOH in vacuo, the crudematerial was passed through silica gel (vacuum, 5% MeOH:CH₂ Cl₂) to givepure product (3.85 g, 26.4%) as an amber oil. DCI/MS (M+1) 313. 400 MHz¹ H NMR (CDCl₃) δ: 7.25 (s, 1H), 6.7-6.8 (m, 2H), 5.9 (s, 2H), 4.6 (m,1H), 3.9 (m, 1H), 3.5 (m, 2H), 3.4 (s, 2H), 2.4-2.7 (m, 10H).

Anal. Calcd. for C₁₅ H₂₁ N₂ O₃ Cl: C, 57.59; H, 6.77; N, 8.95. Found: C,57.24; H, 6.84; N, 8.73

PROCEDURE 71-(1-Chloro-2-hydroxy-3-propanyl)-4-(4-chlorobenzhydryl)piperazineHemihydrate

To a mixture of epichlorohydrin (3.92 mL, 50 mmol) in ethanol (25 mL)and NaHCO₃ (4.2 g, 50 mmol) 4-chlorobenzhydryl piperazine (14.34 g, 50mmol) in EtOH (150 mL) was added dropwise over 45 min at 0° C. undernitrogen. After 20 h, the EtOH was removed in vacuo and the residue waseluted through silica gel using 50% MeOH:CH₂ Cl₂ to give the pureproduct (3.40 g, 18.3%) as a white solid, mp 72°-74° C. DCI/MS (M+1)379; 400 MHz ¹ H NMR (CDCl₃) δ: 7.5-7.35 (m, 9H), 4.2 (s, 1H), 3.65 (m,2H), 2.9 (m, 2H), 2.7-2.6 (m, 8H).

Anal. Calcd. for C₂₀ H₂₄ Cl₂ N₂ O•1/2H₂ O: C, 61.80; H, 6.44; N, 7.20.Found: C, 61.67; H, 6.37; N, 7.10.

PROCEDURE 81-(1-Chloro-2-hydroxy-3-propanyl)-4-[bis(4-chlorophenyl)methyl]piperazine

4,4'-Dichlorobenzhydrylpiperazine ((6.0 g, 18.7 mmol) was reacted asabove with epichlorohydrin to give the title compound as an amber oil,3.67 g (49.8%). 100 MHz ¹ H NMR (CDCl₃) δ: 7.3 (s, 8H), 4.2 (s, 1H), 3.9(m, 1H), 3.6 (d, 2H, J=10 Hz), 2.9 (m, 2H), 2.7-2.4 (m, 10H).

PROCEDURE 91-(1-Chloro-2-hydroxy-3-propoxy)-4-carbethoxypiperazine•Hemihydrate

Carbethoxypiperazine (7.28 mL, 50 mmol) was reacted as above withepichlorohydrin to give the title compound as a clear oil, 8.69 g(69.3%). DCI/MS (M+1) 251; 400 MHz ¹ H NMR (CDCl₃) δ: 4.15 (q, 2H, J=7.1Hz), 3.9 (m, 1H), 3.6 (m, 2H), 3.5 (m, 4H), 2.6-2.4 (m, 4H), 2.5 (d, 2H,J=6.5 Hz), 1.25 (t, 3H, J=7.11 Hz).

Anal. Calcd. for C₁₀ H₁₉ ClN₂ O₃ •1/2H₂ O: C, 46.24; H, 7.76; N, 10.78.Found: C, 46.58; H, 7.47; N, 10.65.

PROCEDURE 101-(1-Chloro-2-hydroxy-3-propanyl)-4-[bis(3,4'-trifluoromethylphenyl)methyl]piperazine•5/4Hydrate

3,4'-Trifluoromethylphenylpiperazine (1.7 g, 4.4 mmol) was reacted asabove with epichlorohydrin to give the title compound as an amber oil,1.23 g (72%). DCI/MS (M+1) 481; 400 MHz ¹ H NMR (CDCl₃) δ: 7.68 (s, 1H),7.6-7.4 (m, 7H), 4.39 (s, 1H), 3.9 (m, 1H), 3.55 (m, 2H), 2.7 (m, 2H),2.55-2.4 (m, 8H).

Anal. Calcd. for C₂₂ H₂₃ ClF₆ N₂ O•5/4H₂ O: C, 52.54; H, 5.11; N, 5.57.Found: C, 52.48; H, 5.41; N, 5.22.

PROCEDURE 111-(1-Chloro-2-hydroxy-3-propanyl)-4-(triphenylmethyl)piperazine•1/4Hydrate

1-(Triphenylmethyl)piperazine (5.25 g, 16 mmol) was reacted as abovewith epichlorohydrin to give the title compound as a white solid, 2.79 g(41.4%), mp 91°-94° C. DCI/MS (M+1) 421; 400 MHz ¹ H NMR (CDCl₃) δ:7.5-7.15 (m, 15H), 3.86 (m, 1H), 3.52 (d, 2H, J=4.85 Hz), 2.9 (m, 2H),2.8-2.4 (m, 10H).

Anal. Calcd. for C₂₆ H₂₉ ClN₂ O•1/4H₂ O: C, 73.39; H, 6.99; N, 6.58.Found: C, 73.34; H, 6.83; N, 6.53.

PROCEDURE 12 1-[Bis(4-chlorophenyl)methyl]piperazine

To 4-chlorobenzhydrol (12.66 g, 50 mmol) in CH₂ Cl₂ (200 mL) undernitrogen, thionyl chloride (10 mL, 137 mmol) was added dropwise over 15min. After 18 h and removal of the solvent in vacuo, the crude productwas dissolved in CH₂ Cl₂ (100 mL) and washed with saturated NaHCO₃ (3×),dried over Na₂ SO₄, and concentrated in vacuo to a thin, amber oil(12.53 g). Upon standing at room temperature for 1 h, crystallizationoccured to give pure product (12.5 g, 88.4%) as a white solid, mp61°-64° C. DCI/MS (M+1) 235. 400 MHz ¹ H NMR (CDCl₃) δ: 7.35 (m, 8H),6.05 (s, 1H).

Anal. Calcd. for C₁₃ H₉ C₁₃ : C, 57.49; H, 3.34. Found: C, 57.69; H,3.46.

This is a known compound: Chem. Abstract., 1957, 51, 9717a.

To piperazine (9.15 g, 106 mmol) in CHCl₃ (200 mL) containing potassiumiodide (2.66 g, 16 mmol) under a nitrogen atmospherebis(4-chlorophenyl)chloromethane (9.5 g, 35 mmol) in CHC₃ (100 mL) wasadded dropwise with stirring over a period of 45 min. After 6 days, thereaction mixture was filtered, concentrated and the crude product waspurified by flash chromatography using 10% MeOH in CH₂ Cl₂ to give thetitle compound as a thick amber oil. 400 MHz ¹ H NMR (CDCl₃) δ: 7.25 (m,8H), 4.25 (s, 1H), 2.9 (m, 4H), 2.3 (m, 4H).

PROCEDURE 13(2S)-(-)-(1,2-Epoxypropyl)-4-[bis(4-fluorophenyl)methyl]piperazine•1/4Hydrate

To NaH (0.9 g, 18.75 mmol, 50% suspension in mineral oil) previouslywashed with pentane in DMF (8 mL) 4,4'-difluorobenzhydrylpiperazine (5.0g, 17.4 mmol) in DMF (15 mL) was added dropwise under nitrogen over 15min at 0° C. After 15 min at 0° C., the mixture was warmed to roomtemperature. After 2 h the mixture was cooled to 0° C.,(2R)-(-)-glycidyl tosylate (4.0 g, 17.5 mmol) in DMF (16 mL) was addeddropwise and the mixture was stirred at room temperature for 24 h undernitrogen. After filtration through celite, the mixture was concentratedin vacuo (1 mmHg, 55° C.) and the residue was dissolved in CH₂ Cl₂.Refiltration of the solution, concentration and flash chromatography ofthe resultant oil through silica gel using 10% MeOH: CH₂ Cl₂ gave thetitle compound as an amber oil, 4.66 g (82.6%); DCI/MS (M+1) 345; 400MHz ¹ H NMR (CDCl₃) δ: 7.4 (m, 4H), 7.0 (m, 4H), 4.25 (s, 1H), 3.1 (m,1H), 2.8 (m, 2H), 2.7-2.4 (m, 8H), 2.3 (m, 2H); [δ]_(D) ²² -7.5° (0.5%in EtOH).

Anal. Calc'd for C₂₀ H₂₂ F₂ N₂ O•1/4H₂ O: C, 68.89; H, 6.50; N, 8.03.Found: C, 69.17; H, 6.53; N, 8.02.

PROCEDURE 14(2R)-(+)-(1,2-Epoxypropyl)-4-[bis(4-fluorophenyl)methyl]piperazineHydrate

Using a similar procedure to that described above, (2S)-(+)-glycidyltosylate (2.0 g, 8.76 mmol) was used to prepare the title compound as anamber oil, 2.57 g (77.8%); DCI/MS (M+1) 345; 400 MHz ¹ H NMR (CDCl₃) δ:7.35 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 3.1 (m, 1H), 2.55 (m, 2H),2.45-2.3 (m, 8H), 2.2 (m, 2H); [δ]_(D) ²² +7.2° (0.5% in EtOH).

Anal. Calc'd for C₂₀ H₂₂ F₂ N₂ O•H₂ O: C, 66.68; H, 6.67; N, 7.73.Found: C, 66.51; H, 6.38; N, 7.73.

PROCEDURE 15 6-Chloro-9-(tetrahydro-2-pyranyl)purine

To a warmed (60° C.) slurry of 6-chloropurine (20 g, 0.1294 mol) andp-toluenesulfonic acid monohydrate (0.35 g), dihydropyran (13.4 mL,0.172 mol) was added with stirring over a period of 30 min. After anadditional 30 min of heating, the mixture was allowed to cool to roomtemperature for 1 h. Concentrated ammonium hydroxide (12 mL) was addedand stirring was continued for 5 min. The solution was washed with water(4×70 mL) and the organic layer was dried (Na₂ SO₄), filtered andconcentrated in vacuo to give a syrup (about 29 g) which slowlycrystallized upon standing. Extraction with boiling hexane gave theproduct as a solid, 24.36 g in two crops (78%), mp 70°-71° C.

Anal. Calcd for C₁₀ H₁₁ ClN₄ O: C, 50.32; H, 4.65; N, 23.47. Found: C,50.25; H, 4.59; N, 23.25.

This is a known compound: R. K. Robins et al., J. Amer. Chem. Soc., 83,2574 (1961).

PROCEDURE 161-(1-Chloro-3-propanyl)-4-[bis(4-fluorophenyl)methyl]piperazine

Pentane (10 mL) was added to sodium hydride (0.50 g, 11 mmol of 50%suspension in mineral oil) and the mixture was stirred under nitrogen.The pentane was decanted. Anhydrous DMF (12 mL) was added and thesuspension was cooled to 0° C. [Bis(4-fluorophenyl)methylpiperazine (2.9g, 10 mmol) in anhydrous DMF (14 mL) was added at 0° C. within 10 min.The reaction mixture was allowed to warm to room temperature. After 1 h,the mixture was cooled to 0° C. and to the light green solution1-chloro-3-bromopropane (5 mL, 50 mmol) in anhydrous DMF (5 mL) wasadded over a period of 10 min. The mixture was stirred under nitrogen atroom temperature for 72 h. The solvents were evaporated in vacuo (1 mmHg) at 50° C. The residue was triturated in methylene chloride andfiltered through celite. The filtrate was washed with water (2× 100 mL),dried (sodium sulfate), filtered, and the filtrate was evaporated invacuo to give crude chloro-propyl compound (3.65 g). Pentane (50 mL) wasadded, and on the next day the pentane insoluble solid was removed byfiltration. The filtrate was evaporated in vacuo to give the titlecompound (2.3 g, 75%) as a clear, colorless oil. 100 MHz ¹ H NMR (CDCl₃)δ: 7.32 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 3.57 (m, 2H), 2.2-2.6 (m,10H), 1.9 (m, 2H). DCI/MS (M+1) 361.

Anal. Calcd. for C₂₀ H₂₃ ClF₂ N₂ : C, 65.83; H, 6.35; N, 7.68. Found: C,65.59; H, 6.42; N, 7.63.

PROCEDURE 171-[1-(2,3-Epoxy)propyl]-4-[bis(4-fluorophenyl)methyl]piperazine

A solution of 4,4'-difluorobenzhydrylpiperazine (28.83 g, 100 mmol) inacetonitrile (250 mL) was added to an ice cold mixture of epibromohydrin(9.1 mL, 110 mmol) and anhydrous potassium carbonate (15.2 g, 110 mmol)in acetonitrile (150 mL) over a period of 40 min. The mixture wasstirred at room temperature for 100 h, filtered and the solids werewashed with methylene chloride. The combined filtrates were concentratedto dryness to give an oil which was eluted through a flashchromatographic silica gel column using 2-3% methanol/methylene chlorideto give the title compound as glass, 23.98 (69.6%); 300 MHz ¹ H NMR(CDCl₃): δ 7.4-6.9 (m, 8H). 4.22 (s. 1H). 3.09 (br m, 1H), 2.8-2.25 (m,12H); MS 345 (MH⁺).

Anal. Calcd. for C₂₀ H₂₂ F₂ N₂ O: C, 69.75; H, 6.44; N, 8.13; F, 11.50.Found: C, 69.73; H, 6.49; N, 8.19; F. 11.66.

PROCEDURE 181-Amino-3-[4-[bis(4-fluorophenyl)methyl]-1-piperazinyl]-2-propanol

A solution of 1-[1-(2,3-epoxy)propyl]-4-[bis(4-fluorophenyl)methyl]piperazine (8.9 g, 25.8 mmol) and liquid ammonia (20 mL) in EtOH (40 mL)was heated in a teflon reaction vessel in a bomb at 110° C. for 28 h.The solution was then evaporated to dryness to give about 10 g of aglass which was purified using flash chromatography on silica gel andincreasing proportions of methanol in methylene chloride to give theproduct as an oil which solidified upon vacuum drying, 5.7 g (61%), mp45°-47° C. IR(neat) 3350 cm⁻¹ ; 300 MHz ¹ H NMR (CDCl₃): δ 7.4-6.9 (m,8H), 4.21 (s, 1H), 3.68 (br m, 1H) 2.8-2.2 (m, 12H); MS 362 (MH⁺).

Anal. Calcd. for C₂₀ H₂₅ F₂ N₃ O: C, 66.46; H, 6.97; N, 11.63. Found: C,66.21; H, 7.10; N, 11.63.

What is claimed is:
 1. A compound of the formula ##STR8## wherein X isselected from S, O, NH, NR₁, wherein R₁ is C₁₋₄ - lower alkyl;M isselected from CH₂, CHOH, CHOCOR₂ and CHOR₂ wherein R₂ is selected fromstraight or branched chain C₁ -C₈ - lower alkyl, phenyl and substitutedphenyl wherein the substituent is C₁ -C₄ - lower alkoxy, CF₃, halo andC₁ -C₄ - lower alkyl, NO₂ and CN; Y is N(CH₂)_(n) -- wherein n is 0-4 orC═; Ar₁, Ar₂ and Ar₃ are independently selected from hydrogen, C₁ -C₄ -lower alkyl, phenyl, substituted phenyl wherein the substituent is C₁-C₄ - lower alkyl, C₁ -C₄ - lower alkoxy, CF₃, halo and perhalo, NO₂ andCN; naphthyl, pyridyl and thienyl; provided that when X is NH or NR₁ andY is N, Ar₁ and Ar₂ are other than hydrogen Z is selected from H, CN,CO₂ R₃ wherein R₃ is H or C₁ -C₄ - lower alkyl; C₁ -C₄ - lower alkyl,halogen and OH; R is selected from H, C₁ -C₄ - lower alkyl; cyclopentyl,cyclohexyl, benzyl, C₂ -C₆ - lower alkenyl, C₂ -C₆ - lower alkynyl,tetrahydropyranyl and tetrahydrofuranyl; Q is selected from halo, amino,C₁ -C₄ - lower alkyl and OH; and the optically active isomers thereof;provided that at least one of Ar₁ Ar₂ and Ar₃ is aromatic and when Y isC═, only Ar₁ and Ar₂ are present.
 2. A compound of claim 1 wherein X isS.
 3. A compound of claim 1 wherein X is O.
 4. A compound of claim 1wherein X is NH or -NH or NR₁.
 5. A compound of claim 1 wherein X is NHor NR₁, wherein R₁ is C₁₋₄ -lower alkyl, Y is N, M is CHOH, Z is H, R isH, and AR₁ and Ar₂ are phenyl or substituted phenyl.
 6. A compound ofclaim 1 wherein X is S, Y is N, M is CHOH, Z is H, R is H, Ar₁ and Ar₂are phenyl or substituted phenyl and AR₃ is H.
 7. A compound of claim 1where X is O, Y is N, M is CHOH, Z is H, R is H, Ar₁ and Ar₂ are phenylor substituted phenyl and AR₃ is H.
 8. A compound of claim 1 whichcompound is6-[1-[1-bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine.9. A compound of claim 1 which compound is(2S)-(+)-6-[1-[1-[bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine.10. A compound of claim 1 which compound is(2R)-(-)-6-[1-[1-[bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine.11. A compound of claim 1 selected from the group consisting of6-[2-hydroxy-3-(1-(diphenylmethyl)piperazin-4-yl)propan-1-yl]mercaptopurine;6-[1-[1-(benzyl)piperazin-4-yl]-2-hydroxy-3-propanylthio]purinemonomalonate;6-[3-[4-(1,3-benzodioxol-5-yl)methyl]piperazin-4-yl]-2-hydroxyprop-1-yl-thio]purine;and6-[1-[1-(4-chlorobenzhydryl)]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine.12. A compound of claim 1 selected from the group consisting of6-[1-[1-(triphenylmethyl)piperazin-4-yl]-2-hydroxy-3-propanylthio]purine;6-[1-[1-[bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-(2,2,2-trimethylacetoxy)propanylthio]purine;6[1-[1-bis(4-fluorophenyl)methyl]piperazin-4-yl)-2-(3,4,5-trimethoxybenzoyloxy)-3-propanylthio]purine;and6-[1-[1-[bis(4-fluorophenyl)methyl]piperazin-4-yl]-3-propanylthio]purine.13. A compound of claim 1 selected from the group consisting of is6-[1-[4-[bis(4'-fluorophenyl)methylene]-1-piperidinyl]-2-hydroxy-3-propanyl-thio]purine;6-[1-[1-[bis-4-chlorophenyl)methyl]-piperazine-4-yl]-2-hydroxy-3-propanylthio]purine;6-[3-[4-[bis(4-fluorophenyl)methyl]piperazin-1-yl]-2-hydroxypropoxy]-9-(tetrahydropyran-2-yl)purine;6-[3-[4-bis(4-fluorophenyl)methyl]-piperazin-1-yl-2-hydroxypurine;6-[3-[4-diphenylmethyl)-piperazin-1-yl]-2-hydroxy-propoxy]-9-(tetrahydro-2-pyranyl)-purine;and 6-[3-[4-diphenylmethyl)piperazin-1-yl]-2-hydroxypropoxy]purine. 14.A pharmaceutical composition comprising a compound of claim 1 of theformula: ##STR9## wherein X is selected from S, O, NH, NR₁, wherein R₁is C₁₋₄ - lower alkyl; M is selected from CH₂, CHOH, CHOCOR₂ and CHOR₂wherein R₂ is selected from straight or branched chain C₁ -C₈ - loweralkyl, phenyl and substituted phenyl wherein the substituent is C₁ -C₄ -lower alkoxy, CF₃, halo, NO₂, CN and C₁ -C₄ - lower alkyl; Y isN(CH₂)_(n) wherein n is 0-4 or C═; Ar₁, Ar₂ and Ar₃ are independentlyselected from hydrogen, C₁ -C₄ - lower alkyl, phenyl, substituted phenylwherein the substituent is C₁ -C₄ - lower alkyl, C₁ -C₄ - lower alkoxy,CF₃, halo and perhalo, NO₂ and CN; naphthyl, pyridyl and thienyl;provided that when X is NH or NR₁ and Y is N, Ar₁ and Ar₂ are other thanhydrogen;Z is selected from H, CN, CO₂ R₃ wherein R₃ is H or C₁ -C₄lower alkyl; C₁ -C₄ - lower alkyl, halogen and OH; R is selected from H,C₁ -C₄ - lower alkyl; cyclopentyl, cyclohexyl, benzyl, C₂ -C₆ loweralkenyl, C₂ -C₆ - lower alkynyl, tetrahydropyranyl andtetrahydrofuranyl; Q is selected from halo, amino, C₁ -C₄ - lower alkyland OH; and the optically active isomers thereof; provided that at leastone of Ar₁ Ar₂ and Ar₃ is aromatic and when Y is C═, only Ar₁ and Ar₂are present; and a pharmaceutically acceptable carrier therefor.
 15. Thecomposition of claim 14 wherein X is S.
 16. The composition of claim 14wherein X is O.
 17. The composition of claim 14 wherein X is NH or NR₁wherein R₁ is C₁₋₄ -lower alkyl.
 18. The composition of claim 14 whereinthe compound is6-[1-[1-bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine.19. The composition of claim 14 wherein the compound is(2s)-(+)-6-[1-[bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine.20. The composition of claim 14 wherein the compound is(2R)-(-)-6-[1-[1-[bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine.21. A method for treating heart disease which comprising administeringan effective amount of a compound of claim 1 of the formula ##STR10##wherein X is selected from S, O, NH, NR₁ wherein R₁ is C₁₋₄ - loweralkyl; M is selected from CH₂, CHOH, CHOCOR₂ and CHOR₂ wherein R₂ isselected from straight or branched chain C₁ -C₈ - lower alkyl, phenyland substituted phenyl wherein the substituent is C₁ -C₄ - lower alkoxy,CF₃, halo, NO₂, CN and C₁ -C₄ - lower alkyl; Y is N(CH₂)_(n) -- whereinn is 0-4 or C═; Ar₁, Ar₂ and Ar₃ are independently selected fromhydrogen, C₁ -C₄ - lower alkyl, phenyl, substituted phenyl wherein thesubstituent is C₁ -C₄ - lower alkyl, C₁ -C₄ - lower alkoxy, CF₃, haloand perhalo, NO₂ and CN; naphthyl, pyridyl and thienyl; provided thatwhen X is NH or NR₁ and Y is N, Ar₁ and Ar₂ are other than hydrogen;Z isselected from H, CN, CO₂ R₃ wherein R₃ is H or C₁ -C₄ - lower alkyl; C₁-C₄ - lower alkyl, halogen and OH; R is selected from H, C₁ -C₄ - loweralkyl; cyclopentyl, cyclohexyl, benzyl, C₂ -C₆ - lower alkenyl, C₂ -C₆ -lower alkynyl, tetrahydropyranyl and tetrahydrofuranyl; Q is selectedfrom halo, amino, C₁ -C₄ - lower alkyl and OH; and the optically activeisomers thereof; provided that at least one of Ar₁ Ar₂ and Ar₃ isaromatic and when Y is C═, only Ar₁ and Ar₂ are present.
 22. The methodof claim 21 wherein the compound is selected from6-[1-[1-bis(4fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine;(2S)-(+)-6-[1-[bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purineand(2R)-(-)-6-[1-[1-[bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine.23. The method of preventing cardiac arrythmia which comprisesadministering an effective amount of a compound of claim 1 of theformula: ##STR11## wherein X is selected from S, O, NH, NR₁, wherein R₁is C₁₋₄ - lower alkyl; M is selected from CH₂ CHOH, CHOCOR₂ and CHOR₂wherein R₂ is selected from straight or branched chain C₁ -C₈ - loweralkyl, phenyl and substituted phenyl wherein the substituent is C₁ -C₄ -lower alkoxy, CF₃, halo, NO₂, CN and C₁ -C₄ - lower alkyl; Y isN(CH₂)_(n) -- or C═; Ar₁, Ar₂ and Ar₃ are independently selected fromhydrogen, C₁ -C₄ - lower alkyl, phenyl, substituted phenyl wherein thesubstituent is C₁ -C₄ - lower alkyl, C₁ -C₄ - lower alkoxy, CF₃, haloand perhalo, NO₂ and CN; naphthyl, pyridyl and thienyl; provided thatwhen X is NH or NR₁ and Y is N, Ar₁ and Ar₂ are other than hydrogen;Z isselected from H, CN, CO₂ R₃ wherein R₃ is H or C₁ -C₄ lower alkyl; C₁-C₄ - lower alkyl, halogen and OH; R is selected from H, C₁ -C₄ loweralkyl; cyclopentyl, cyclohexyl, benzyl, C₂ -C₆ - lower alkenyl, C₂ -C₆ -lower alkynyl, tetrahydropyranyl and tetrahydrofuranyl; Q is selectedfrom halo, amino, C₁ -C₄ - lower alkyl and OH; and the optically activeisomers thereof; provided that at least one of Ar₁ Ar₂ and Ar₃ isaromatic and when Y is C═, only Ar₁ and Ar₂ are present.
 24. The methodof claim 21 wherein the compound is selected from6-[1-[1-bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine;(2S)-(+)-6-[1-[bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine;and(2R)-(-)-6-[1-[1-[bis(4-fluorophenyl)methyl]piperazin-4-yl]-2-hydroxy-3-propanylthio]purine.